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(BQ) Part 2 book Pain control presents the following contents: Plasticity of inhibition in the spinal cord, modulation of peripheral inflammation by the spinal cord, the role of proteases in pain, amygdala pain mechanisms, itch and pain differences and commonalities,...
The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain Elizabeth Amy Old, Anna K Clark, and Marzia Malcangio Contents Origin and Function of Glia Acute and Chronic Pain 2.1 Inflammatory and Neuropathic Pain Spinal Glia Changes in Models of Neuropathic Pain 3.1 Microglial Responses to Injury or Insult 3.2 Astrocytic Responses to Injury or Insult 3.3 CX3CL1, CX3CR1 and Cathepsin S 3.4 TNF and TNFR 3.5 IL-1β and IL-1R Spinal Glia During Inflammatory Pain Spinal Glia During Rheumatoid Arthritis Pain Concluding Remarks References 146 148 149 150 150 152 153 154 156 157 158 160 161 Abstract Chronic pain, both inflammatory and neuropathic, is a debilitating condition in which the pain experience persists after the painful stimulus has resolved The efficacy of current treatment strategies using opioids, NSAIDS and anticonvulsants is limited by the extensive side effects observed in patients, underlining the necessity for novel therapeutic targets Preclinical models of chronic pain have recently provided evidence for a critical role played by glial cells in the mechanisms underlying the chronicity of pain, both at the site of damage in the periphery and in the dorsal horn of the spinal cord Here microglia and astrocytes respond to the increased input from the periphery and change morphology, increase in number and release pro-nociceptive mediators such as E.A Old • A.K Clark • M Malcangio (*) Wolfson Centre for Age Related Diseases, King’s College London, London, UK e-mail: marzia.malcangio@kcl.ac.uk # Springer-Verlag Berlin Heidelberg 2015 H.-G Schaible (ed.), Pain Control, Handbook of Experimental Pharmacology 227, DOI 10.1007/978-3-662-46450-2_8 145 146 E.A Old et al ATP, cytokines and chemokines These gliotransmitters can sensitise neurons by activation of their cognate receptors thereby contributing to central sensitization which is fundamental for the generation of allodynia, hyperalgesia and spontaneous pain Keywords Glia • Microglia • Astrocytes • Neuropathic pain • Inflammatory pain • Spinal cord • CX3CL1/R1 • IL-1β • TNF • Rheumatoid arthritis Origin and Function of Glia The term neuroglia was coined to describe the interstitial substance surrounding neurons of the CNS (central nervous system) and was later determined to consist of distinct neuroglial cells The name astrocyte was introduced to describe ‘starshaped’ neuroglial cells which were observed to form the supportive system of the CNS A third cellular element of the CNS was acknowledged in 1913 when improved staining techniques for neuroglial cells led to the recognition of non-neuronal cells that were distinct from astrocytes During the 1920s del Rio-Hortega employed silver carbon staining and light microscopy to visualise a population of cells that appeared different from the macroglia (oligodendrocytes and astrocytes) that had previously been described in the CNS These cells, termed microglia, were thought to arise either from CNS invasion of blood mononuclear (monocytic) cells or mesodermal pial elements (Del Rio-Hortega 1932, 2012a, b; Kettenmann et al 2011; Prinz and Mildner 2011) Whilst alternatives for the origin of microglia have been hypothesised, evidence to support the hypothesis that these cells are of monocytic lineage was later strengthened using autoradiography Leblond and colleagues demonstrated that microglia possess specific monocytic characteristics, specifically the ability to transform from an amoeboid to a ramified cell (Imamoto and Leblond 1978; Ling et al 1980) The monocytic/myeloid origins of microglia has now been confirmed conclusively by the absence of microglia from the CNS of a genetically altered mouse strain that lack PU.1, a key transcription factor in the control of myeloid cell differentiation (McKercher et al 1996; Beers et al 2006) Microglia appear at an early stage during embryogenesis where they originate from macrophages in the foetal yolk sac that migrate into the CNS (Saijo and Glass 2011); evidence from postnatal fluorescently labelled cells demonstrates that in this phase of development, microglia are capable of differentiating from monocytes entering the CNS from the circulation (Perry et al 1985) Conversely, in adult rodents, circulating monocytes only enter the CNS under conditions where there is disruption to the blood-brain barrier (BBB) (King et al 2009); however, as demonstrated by the use of immune-irradiated mice, the CNS colonisation by these cells is transient and does not contribute to the resident microglial cell pool The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain 147 (Ajami et al 2011) Rather the microglial population is maintained locally and independently of circulating monocytes via the proliferation of existing cells (Lawson et al 1992; Ginhoux et al 2010) Microglia are specialised phagocytes of the CNS and constitute 5–20 % of the total glial cell population (Saijo and Glass 2011) Under physiological conditions microglia exist in a ‘resting’ or ‘quiescent’ state; these cells can be distinguished morphologically by their small soma and ramified process that perform immune surveillance of the surrounding area Additionally they express receptors for complement components (Fcγ receptor of IgG) and exhibit low expression of cell surface antigens (Nimmerjahn et al 2005) Several mechanisms by which these cells maintain a quiescent state have been proposed, including interaction of microglial CX3CR1 receptor with its neuronal ligand the chemokine CX3CL1 and inhibitory signalling through the microglial cell surface proteins CD172, CD200R and CD45 with their neuronal ligands CD47, CD200 and CD22, respectively (Ransohoff and Perry 2009; Ransohoff and Cardona 2010; Cardona et al 2006; Saijo and Glass 2011) Within the healthy CNS, microglia have a number of key roles in addition to their function as immune surveyors As well as monitoring extrasynaptic regions, microglial processes transiently contact synapses, including presynaptic terminals and perisynaptic clefts (Tremblay et al 2010) Additionally these cells possess a number of neurotransmitter receptors; combined these attributes allow microglia to monitor synaptic function (Salter and Beggs 2014) Microglial cells are present in the CNS from the early stages of development and due to their phagocytic capacity are able to contribute to the elimination of excess neurons that form as part of normal development (Marin-Teva et al 2011) However, rather than simply removing waste, microglia can initiate apoptosis of cells via the release of several factors including superoxide ions and TNF (Marin-Teva et al 2004; Sedel et al 2004; Salter and Beggs 2014) Additionally, a number of inappropriate synaptic connections are made between neurons during development, and microglia play an important role in the regulation of these contacts via the process of synaptic pruning—the phagocytosis of both pre- and postsynaptic elements in a complement cascade-dependent manner (Salter and Beggs 2014; Stevens et al 2007; Schafer et al 2012) Microglia contribute to the maturation of established synapses; the functional properties of synapses develop abnormally in mice deficient in several microglial proteins, including CX3CR1, for example, the absence of which results in increased excitatory neurotransmission (Paolicelli et al 2011; Salter and Beggs 2014) The involvement of microglia to the maintenance of synaptic plasticity has also been investigated in the adult CNS, where they contribute to both homeostatic and activity-triggered plasticity by releasing a number of mediators such as TNF and TGFβ (Butovsky et al 2014; Koeglsperger et al 2013) Of all of the glial cell populations within the CNS, astrocytes are by far the most abundant In mammals astrocytogenesis begins in late embryogenesis and continues into the postnatal phase The origin of astrocytes is likely diverse, varying throughout the stages of development For example, within the cerebral cortex, astrocytes develop from two distinct sources: from radial glia in the ventricular 148 E.A Old et al zone during embryogenesis and from subventricular zone (SVZ) progenitors during the postnatal period (Wang and Bordey 2008) Additionally, studies using in vivo retroviral gene transfer have demonstrated that SVZ progenitors can generate both grey and white matter astrocytes as well as oligodendrocytes (Levison and Goldman 1993, 1997; Levison et al 1993) The typical image of an astrocyte is that of a stellate cell; however, astrocytes have a complex and heterogeneous morphology (Wang and Bordey 2008) Whilst the nomenclature is considered outdated by some, astrocytes are typically classified into one of two subtypes, protoplasmic and fibrous, where the former are found throughout the grey matter and possess branches that give rise to uniformly distributed processes and the latter are distributed within the white matter and exhibit long fibrelike processes (Sofroniew and Vinters 2010) Furthermore, the branching processes of protoplasmic astrocytes envelop synapses and have endfeet that encase blood vessels, whilst the endfeet of the unbranched processes of fibrous astrocytes envelop nodes of Ranvier (Wang and Bordey 2008) Immunohistochemically astrocytes are commonly identified by the presence of glial fibrils, the major component of which is glial fibrillary acidic protein (GFAP) Antibodies against S100B, a member of the S100 family of EF-band calcium binding proteins, are also used to identify astrocytes; however, this antigen is only expressed by a subset of mature astrocytes Thus, its expression is not representative of the astrocyte population as a whole (Baudier et al 1986; Deloulme et al 2004; Hachem et al 2005) Due to the absence of several biophysical properties such as the ability to generate action potentials under physiological conditions, astrocytes were once described as passive (Steinhauser et al 1992); however, this term is now rarely used Whilst the initial function of astrocytes was understood to be as little more than an inert scaffold to neurons, it is now widely accepted that they play a critical role in a vast number of processes within the CNS (Volterra and Meldolesi 2005) The close association of astrocytes with many neuronal elements allows astrocytes to regulate the extraneuronal environment around synapses and provide support and nourishment to these cells (Gao and Ji 2010), for example, by buffering extracellular potassium and glutamate Additionally astrocytes have been demonstrated to significantly contribute to neuronal survival and maturation (via the synthesis and release of growth and trophic factors such as NGF), synapse formation and the regulation of angiogenesis and are a major source of adhesion and extracellular matrix proteins within the CNS that can both promote and inhibit neurite growth (Wang and Bordey 2008) Acute and Chronic Pain Pain is a subjective sensory experience associated with actual or potential tissue damage (www.iasp.org) It is always unpleasant and therefore an emotional experience Acute pain is mediated by multi-synaptic pathways beginning with specialised primary afferent fibres (nociceptors) in the periphery, whose cell bodies The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain 149 lie in the dorsal root ganglia (DRG), via the dorsal horn of the spinal cord to supraspinal sites such as the parabrachial area (PBA), periaqueductal grey (PAG), thalamus and cortex The nociceptors convert the energy of noxious stimuli into electrical impulses which are transmitted to the dorsal horn of the spinal cord Within the spinal cord, nociceptive transmission is mediated predominately by glutamate acting upon postsynaptic ionotropic receptors; however, the co-release of substance P and calcitonin gene-related peptide (CGRP) and the subsequent activation of their respective NK1 and CGRP receptors postsynaptically modulates glutamatergic transmission (Go and Yaksh 1987; Cheunsuang and Morris 2000; Malcangio and Bowery 1994; Lever et al 2003; Oku et al 1987; Seybold et al 2003) Modulatory control of acute pain is provided by descending inhibitory and facilitatory pathways from the brain and from inhibitory and excitatory interneurons within the spinal cord (Todd 2010; D’Mello and Dickenson 2008) Acute pain is a vital protective mechanism that persists only for the duration of tissue damage or the presence of a noxious stimulus Evidence for the importance of acute pain is provided by individuals expressing the rare phenotype of insensitivity to pain; these patients experience regular inadvertent self-mutilation through injury and have a significantly lower than average life expectancy (Cox et al 2006; Verpoorten et al 2006) Commonly pain outlives its usefulness and becomes chronic pain, which is profoundly different from acute pain, as it is the result of plastic changes within the pain pathways Chronic pain is a debilitating condition lasting longer than months from the noxious stimuli and causes pain to be perceived as out of proportion to the initial inciting injury Chronic pain can be classified into different types depending on its cause: inflammatory pain is commonly due to tissue inflammation as observed in arthritis, and neuropathic pain arises upon injury to the nervous system 2.1 Inflammatory and Neuropathic Pain In both cases a combination of mechanisms results in augmented nociceptive transmission due to peripheral and central sensitisation Neuropathic pain is that arising from a lesion to the PNS (peripheral nervous system) or CNS as a consequence of physical trauma or disease pathogenesis Chronic inflammatory pain is typically associated with inflammatory diseases such as arthritis, where the presence of algogenic mediators results in nociceptor sensitisation in the affected tissue, such as the joints in the case of arthritis Chronic pain is characterised by the presence of a range of symptoms including hyperalgesia (increased sensitivity to noxious stimuli), allodnyia (a painful response to a previously innocuous stimuli) and spontaneous pain (Woolf and Mannion 1999) The treatment of chronic pain is a substantial problem within the clinic as many patients not respond adequately to available analgesics The difficulty in treating chronic pain conditions is thought to be a consequence of the heterogeneity of the molecular mechanisms underlying the development and maintenance of chronic pain, many of which are not well understood 150 E.A Old et al The mechanisms by which these maladaptive pain states arise can be categorised into peripheral sensitisation (changes in peripheral nerves) and central sensitisation (including immune responses in the spinal cord) Peripheral sensitisation due to injury to a localised area leads to primary hyperalgesia and results in increased nociceptive transmission from the periphery which causes changes in dorsal horn neuron activation Dorsal horn neurons exhibit reduced thresholds to noxious stimuli applied to the periphery, de novo excitation by previously innocuous stimuli, expansion of their receptive fields and increased spontaneous activity These changes increase excitability of CNS neurons and result in central sensitisation, which is fundamental for the generation of allodynia, secondary hyperalgesia and spontaneous pain (Kuner 2010; Latremoliere and Woolf 2009; Sandkuhler 2009) The resulting increase in glutamate released from central terminals of sensitised neurons trigger phosphorylation of NMDA receptors and post-translational modifications of neuronal proteins Glial cells within the spinal cord respond to the enhanced nociceptive input by proliferating and switching to a responsive state whereby they release mediators which contribute to dorsal horn mechanisms of chronic pain (Clark and Malcangio 2012; Old and Malcangio 2012) Enhanced activity within the spinal cord triggers cortical and subcortical structures to facilitate excitation and signalling and constitutes higher centre modulation (D’Mello and Dickenson 2008) Here we will describe and define some of the key mechanisms by which microglia and astrocyte responses in the dorsal horn contribute to the development and maintenance of chronic neuropathic and inflammatory pain states, with a specific focus on chemokine/cytokine signalling and second messenger activation Spinal Glia Changes in Models of Neuropathic Pain 3.1 Microglial Responses to Injury or Insult Microglia are the resident immune cells of the CNS and as such respond to pathological insult or tissue injury and subsequent release of mediators from damaged cells These cells respond to a number of mediators that are increased in the dorsal horn following peripheral injury They express receptors for the neurotransmitters released from the central terminals of primary afferents: glutamate NMDA and AMPA receptors, the SP receptor NK1 and the CGRP receptor, TrkB receptors for brain derived neurotrophic factor (BDNF) and purinergic receptors including P2X7 and P2X4, many of which are upregulated following injury to the periphery (Rasley et al 2002; Pezet et al 2002; McMahon and Malcangio 2009; Ransohoff and Perry 2009) Microglia respond quickly to an insult by proliferating to expand their population; this process is often termed microgliosis An insult need not be central in nature, for example it could be the result of a CNS infection or spinal cord injury In rodent peripheral nerve injury models of neuropathic pain, microglia within the dorsal horn of the spinal cord respond swiftly to augmented primary afferent fibre The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain 151 input This phenotypic shift is often referred to as the ‘activation’ of microglia Input from the periphery is vital for this process; blockade of peripheral nerve conduction by the application of a local anaesthetic prevents nerve injury-induced microglial response (Wen et al 2007; Hathway et al 2009; Suter et al 2009) In the region of the dorsal horn in which the injured primary afferents terminate, microglia increase in their numbers and appear more amoeboid, with a hypertrophied soma and thick retracted processes Additionally they alter their expression of cell surface antigens that play a critical role in immune responses; for example, MHC class II is increased allowing the presentation of antigens by microglia (McMahon and Malcangio 2009) Activated microglia also synthesise and release a variety of pro-nociceptive mediators into the extracellular environment, including cytokines (e.g TNF and IL-1β), chemokines (e.g CCL2), reactive oxygen species (ROS) and nitric oxide (NO) Prominent signalling pathways in the development of neuropathic pain are the CX3CR1/L1 loop (discussed below) and the purinergic pathway of microglial activation and subsequent BDNF release ATP is known to stimulate microglia both in vivo and in vitro via purinergic receptors on the surface membrane of the cells (Honda et al 2001; Tsuda et al 2003, 2012; Davalos et al 2005) Microglial P2X4 is of particular importance for the development of neuropathic pain; it is upregulated in microglia as early as 24 hours after peripheral nerve injury, and the pharmacological inhibition of this receptor transiently attenuates mechanical allodynia in rodents Furthermore, the intrathecal administration of ATP-treated microglia in naive mice results in the development of mechanical hypersensitivity (Tsuda et al 2003; Coull et al 2005) Current evidence indicated that downstream effects of the activation of microglial purinergic receptors are mediated by the release of BDNF via the phosphorylation of p38 MAPK; the administration of an inhibitor of the BDNF receptor, TrkB, prevents the behavioural changes observed following the administration of activated microglia (Coull et al 2005), and a p38 MAPK inhibitor is able to prevent release of BDNF from microglia (Trang et al 2009) The temporal profile of microglial activation within the spinal cord is well documented in models of neuropathic pain Real-time PCR of spinal cord tissue extracts demonstrates alterations in the levels of microglia-specific mRNA transcripts (e.g TLR4 and CD14) within hours of injury (Tanga et al 2004), and the phosphorylation of the microglial MAPK p38 is evident within minutes from peripheral nerve injury (Svensson et al 2005b; Clark et al 2007b) Morphological changes (the presence of amoeboid cells and increased immunoreactivity for the microglial marker Ox42) have been observed immunohistochemically as early as days after nerve injury and are maintained for at least 50 days post-surgery (Clark et al 2007a) Furthermore, the temporal profile of microglial activation is concomitant to the development of behavioural hypersensitivity (Clark et al 2007b; Zhang et al 2007; Peters et al 2007) and the intrathecal administration of compounds that inhibit glial activation to neuropathic rodents is able to attenuate pain behaviours (Clark et al 2007a; Tawfik et al 2007), demonstrating that the activation of these cells does indeed contribute to aberrant pain signalling 152 3.2 E.A Old et al Astrocytic Responses to Injury or Insult Due to their many functions in the maintenance of CNS homeostasis, under physiological conditions astrocytes are often referred to as ‘active’ Following a change in their environment, such as that occurring in the spinal cord in models of chronic pain, these cells shift to a ‘reactive’ phenotype; astrocytes undergo hypertrophy and increase their expression of a number of cellular proteins including GFAP, S100β and vimentin, which are consequently often used as markers of astrocyte reactivity (Ridet et al 1997; Pekny and Nilsson 2005) This process is referred to as astrogliosis and has been demonstrated in a number of surgical models of neuropathic pain (Garrison et al 1991; Colburn et al 1999; Sweitzer et al 1999) Astrocyte reactivity can occur through the activation of several pathways; these cells express the receptors for the neurotransmitters NMDA, SP and CGRP (Porter and McCarthy 1997) and thus respond to increased transmitter release in the dorsal horn of the spinal cord subsequent to peripheral nerve injury In addition, astrocytes possess a variety of cytokine and chemokine receptors that can be activated by their ligands released from microglia; key examples include IL-18/ IL-18R, TNF/TNFR and CCL2/CCR2 (Miyoshi et al 2008; Gao et al 2009, 2010b) One of the astrocytic changes most likely to be responsible for the contribution of these cells to the maintenance of pain is a decrease in the glutamate transporters GLT1 and GLAST These transporters function to regulate extracellular glutamate concentrations at non-toxic levels A decrease in their expression or function results in an elevation in the concentration of spinal extracellular glutamate which can elicit nociceptive hypersensitivity via the activation of NMDA and AMPA receptors (Liaw et al 2005; Weng et al 2006) Recent evidence indicates that astrocytes, like microglia, play a critical role in aberrant pain signalling, as the administration of glial inhibitors, such as fluorocitrate, attenuates pain behaviours in rodents (Milligan et al 2003; Watkins et al 1997; Okada-Ogawa et al 2009) Interestingly, the intrathecal administration of reactive astrocytes, briefly incubated with TNF, induces the development of mechanical allodynia in uninjured mice (Gao et al 2010b) As with microglia, the temporal profile of astrocyte activation has been assessed; astrogliosis becomes apparent after the microglial response, several days after peripheral nerve injury, and lasts for over weeks post-injury (Colburn et al 1999; Tanga et al 2004; Romero-Sandoval et al 2008) Additionally genetically altered mice that are deficient in GFAP develop a shorter lasting mechanical allodynia than their wild-type counterparts Finally the administration of a GFAP antisense mRNA that prevents translation of GFAP reverses established mechanical allodynia when administered to rats weeks following a peripheral nerve injury (Kim et al 2009) Together these data demonstrate a role for astrocytes in the maintenance of neuropathic pain The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain 3.3 153 CX3CL1, CX3CR1 and Cathepsin S CX3CL1, also known as fractalkine, is the only member of the CX3C family of cytokines The cx3cl1 gene was originally described as abundant in the brain and heart but present in all tissues assessed, except peripheral blood leukocytes (Pan et al 1997) Recent evidence obtained from a series of in situ hybridisation and immunohistochemical studies has determined that neurons are the principle source of CX3CL1 in the CNS (Hughes et al 2002; Nishiyori et al 1998; Tarozzo et al 2003) Additionally, the development of a transgenic mouse expressing a red fluorescent reporter under the control of the CX3CL1 promoter has demonstrated that within the spinal cord CX3CL1 is expressed in dorsal horn neurons (Kim et al 2011) Both the CX3CL1 protein and mRNA are expressed here, but the protein is not upregulated following peripheral nerve injury (Verge et al 2004; Clark et al 2009; Lindia et al 2005) Furthermore, it has been demonstrated that cytoplasmic glutamate-containing vesicles are present within CX3CL1-positive neurons, indicating that CX3CL1 is expressed within excitatory neurons (Tong et al 2000) First described as a potent chemoattractant of T-cells and monocytes in the late 1990s (Bazan et al 1997; Pan et al 1997), CX3CL1 exists in two forms As a membrane-tethered protein it plays a critical role in the firm adhesion of leukocytes to the endothelium to facilitate transmigration (Imai et al 1997; Fong et al 1998; Corcione et al 2009) Soluble CX3CL1 is produced by metalloproteases (ADAM10/17) or protease (Cathepsin S) -mediated cleavage of membrane-bound CX3CL1 Whilst ADAM 10 is responsible for constitutive shedding of CX3CL1, ADAM 17 facilitates inducible shedding of this protein (Bazan et al 1997; Hundhausen et al 2003, 2007; Clark et al 2011) Cathepsin S, on the other hand, is expressed by antigen-presenting cells such as microglia where its release is dependent on the activation of the purinergic receptor P2X7 (Clark et al 2010) and is enhanced by pro-inflammatory mediators (Liuzzo et al 1999a, b) CX3CL1 exerts its biological effects by binding to CX3CR1 for which it is the only ligand Expression analysis of CX3CR1 has demonstrated its mRNA to be abundant in the spleen and peripheral blood leukocytes as well as the brain Furthermore, the expression of CX3CR1 mRNA is tenfold higher in cultured microglial than whole brain samples, suggesting the receptor is of microglial origin FACS analysis and calcium imaging of microglia have demonstrated that these cells possess the functional CX3CR1 protein as well as the mRNA (Harrison et al 1998) This expression profile of CX3CR1 has been confirmed conclusively by the development of a transgenic mouse in which the CX3CR1 contains a green fluorescent protein reporter allowing visualisation of the transcribed protein; here, in the mouse, CX3CR1 protein was observed in microglia throughout the CNS but was not present in astrocytes or oligodendrocytes (Jung et al 2000) Within the CNS the CX3CL1–CX3CR1 interaction contributes the maintenance of a quiescent phenotype in microglia and suppresses the release of pro-inflammatory mediators (Mizuno et al 2003; Lyons et al 2009) As such, under these conditions, this protein–protein relationship is thought to be 154 E.A Old et al neuroprotective In the context of chronic pain, several observations support a pro-nociceptive role of CX3CL1 The administration of the soluble chemokine domain of CX3CL1 into the intrathecal space at the lumbar level is pro-nociceptive and causes otherwise naive animals to exhibit nocifensive behaviours (Zhuang et al 2007; Clark et al 2007b; Milligan et al 2004, 2005a) Consistently, the intrathecal administration of anti-CX3CL1 antibodies to neuropathic rodents attenuates pain-related behaviour (Clark et al 2007b) Interestingly, the CSF levels of CX3CL1 increase in neuropathic animals compared to sham controls (Clark et al 2007b, 2009) CX3CR1 exhibits similar pro-nociceptive attributes under aberrant pain conditions Enhanced expression of the protein within the dorsal horn of the spinal cord is associated with microgliosis following peripheral nerve injury (Zhuang et al 2007; Staniland et al 2010) One mechanism described is IL-6 dependent; IL-6 mRNA and protein expression is induced in neurons following the peripheral nerve injury (Arruda et al 1998; Lee et al 2009), and prophylactic treatment with an IL-6 neutralising antibody prevents increased CX3CR1 expression, whilst, conversely, the administration of recombinant IL-6 significantly augments CX3CR1 expression (Lee et al 2010) Supporting a pro-nociceptive role of CX3CR1 and a critical role for CX3CL1–CX3CR1 interaction in the development of pathological pain responses, CX3CR1-deficient mice not develop hyperalgesia and/or allodynia in models of nerve injury and exhibit reduced microgliosis when compared to their wild-type littermate controls (Staniland et al 2010) Similarly, the intrathecal administration of an antiCX3CR1 antibody attenuates both the behavioural and microglial responses to injury (Zhuang et al 2007; Milligan et al 2004, 2005a) Within spinal cord microglia activation of CX3CR1 by CX3CL1 results in increased intracellular calcium concentrations (Harrison et al 1998), the phosphorylation of p38 MAPK and subsequent release of pro-nociceptive molecules such as IL-6, NO and IL-1β (Zhuang et al 2007; Clark et al 2007b) 3.4 TNF and TNFR TNF, previously known as TNFα, is a small pro-inflammatory cytokine first described in activated macrophages as a molecule with tumour-regression activity (Carswell et al 1975) TNF belongs to a superfamily of ligand/receptor proteins that share a structural motif — the TNF homology domain The TNF receptors are the other members of this family of proteins; two have been identified and are either constitutively expressed (TNFR1/p55-R) or inducible (TNFR2/p75-R) (Bodmer et al 2002; Leung and Cahill 2010) Under physiological conditions TNF is expressed at very low levels in the spinal cord; however, it is rapidly upregulated in both microglia and astrocytes (glia) and neurons following peripheral injury (DeLeo et al 1997; Ohtori et al 2004; Hao et al 2007; Youn et al 2008) Similarly both TNFR1 and TNFR2 are expressed within glia and neurons in the spinal cord (Gruber-Schoffnegger et al 2013; Ohtori et al 2004; Hao et al 2007) The use of receptor-specific protein ligands has demonstrated that it is TNFR1 activation in the 294 M Schmelz Fig (a) Pre-sensitization with nerve growth factor (NGF, μg) injected weeks before UV-B irradiation (threefold minimum erythema dose) provoked spontaneous pain ratings following the intensity of the UV-induced inflammation (b) Hyperalgesia to pinprick stimuli develops following intradermal NGF injection and also for about days after UV-B irradiation Combined sensitization with NGF and UV-B irradiation causes a supra-additive increase of mechanical hyperalgesia Modified from Rukwied et al (2013b) (Vogelsang et al 1995), indicating that pain-induced inhibition of itch might be compromised in these patients The exact mechanisms and roles of central sensitization for itch in specific, clinical conditions have still to be explored, whereas a major role of central sensitization in patients with chronic pain is generally accepted It should be noted that in addition to the parallels between experimentally induced secondary sensitization phenomena, there is also emerging evidence for corresponding phenomena in patients with chronic pain and chronic itch In patients with neuropathic pain, it has been reported that histamine iontophoresis resulted in burning pain instead of pure itch which would be induced by this procedure in healthy volunteers (Birklein et al 1997; Baron et al 2001) This phenomenon is of special interest as it demonstrates spinal hypersensitivity to C-fiber input Conversely, normally painful electrical, chemical, mechanical, and thermal stimulation is perceived as itching when applied in or close to lesional skin of atopic dermatitis patients (Heyer et al 1995; Steinhoff et al 2003) Ongoing activity of pruriceptors, which might underlie the development of central sensitization for itch, has already been confirmed microneurographically in a patient with chronic pruritus (Schmelz et al 2003a) Thus, there is emerging evidence, for a role of central sensitization for itch in chronic pruritus While there is obviously an antagonistic interaction between pain and itch under normal conditions, the patterns of spinal sensitization phenomena are surprisingly similar It remains to be established whether this similarity will also include the underlying mechanism which would also implicate similar therapeutic approaches Itch and Pain Differences and Commonalities 295 such as gabapentin (Dhand and Aminoff 2014) or clonidine (Elkersh et al 2003) for the treatment of neuropathic itch 2.2 Peripheral Sensitization There is cumulative evidence for a prominent role of nerve growth factor (NGF)induced sensitization of primary afferents in both chronic itch and pain: increased levels of NGF were found in chronic itch patients suffering from atopic dermatitis or psoriasis (Toyoda et al 2002, 2003; Tominaga et al 2009; Yamaguchi et al 2009) Similarly, there is clear evidence for a major role of NGF in chronic inflammatory pain (Chevalier et al 2013; Watanabe et al 2011; Barcena de Arellano et al 2011) Moreover, blocking NGF by specific antibodies proved to be analgesic in the chronic pain patients (Lane et al 2010; Sanga et al 2013) AntiNGF strategies also were successful in animal models of chronic itch (Tominaga and Takamori 2014) It is therefore not surprising that intradermally injected NGF not only causes hyperalgesia to heat and mechanical stimuli in volunteers (Hirth et al 2013; Rukwied et al 2010) but also sensitizes for cowhage-induced itch (Rukwied et al 2013c) Intracutaneous NGF injection does not induce visual inflammatory responses in human (Rukwied et al 2010), but interestingly, when combined with an inflammatory pain model (UV-B sunburn), the subjects report of spontaneous pain (Fig 3) and pronounced hyperalgesia (Rukwied et al 2013b) that also includes axonal hyperexcitability (Rukwied et al 2013a) These results nice match the analgesic effects of anti-NGF in chronic inflammatory pain that are not accompanied by reduced signs of inflammation (Lane et al 2010) Therefore, it emerges that neurotrophic factors such as NGF can change expression patterns of primary afferent nociceptors such that their ability to signal pain or itch by local inflammatory mediators is increased This increase might be based on higher discharge frequencies linked to sensitized transduction, but also to axonal hyperexcitability Perspectives: Mechanisms for Itch or Pain in Neuropathy and Chronic Inflammation Finally, the current concepts differentiating itch and pain need to be evaluated in view of the obvious clinical questions concerning the development of itch or pain after neuropathy or in chronic inflammatory diseases It is remarkable that some neuropathic conditions such as postherpetic neuralgia and diabetic neuropathy are primarily linked to pain symptoms whereas patients suffering from notalgia paresthetica or brachioradial pruritus mainly report chronic itch (Table 1) It is important to note that more than 25 % of patients with neuropathic pain conditions such as postherpetic neuropathy also report itch (Oaklander et al 2003) According to the specificity or selectivity theory, one would hypothesize that the mediators being released in diabetic neuropathy or postherpetic neuralgia 296 Table Summary of neuropathic conditions and their dominant symptoms M Schmelz Postherpetic neuralgia Diabetic neuropathy Meralgia paresthetica Notalgia paresthetica Brachioradial pruritus Pain +++ ++(+) +++ (+) (+) Itch ++ + (+) +++ +++ determine to which extent itch-selective or itch-specific primary afferents are excited Moreover, itching neuropathic conditions such as nostalgia paresthetica and brachioradial pruritus should be differentiated from painful meralgia paresthetica by primary activation of pruriceptors rather than nociceptors However, it is completely unclear how such differentiation could be mediated for very similar peripheral neuropathic conditions Possibly, specific pruriceptors only play a minor role under these conditions In contrast, the spatial pattern of nociceptor activation might provide the crucial input: if only few scattered axons are spontaneously active, their input might mimic the one of scattered nociceptors being activated by cowhage spicules in the epidermis, whereas activation of numerous nociceptors of a peripheral nerve would result in pain Thus, such itch sensation would be generated by the particular spatial code of activated nociceptors (Schmelz and Handwerker 2013; 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Differences and Commonalities 301 prostatitis/chronic pelvic pain syndrome is correlated with symptom severity and response to treatment BJU Int 108(2):248–251 Wooten M, Weng HJ, Hartke TV, Borzan J, Klein AH, Turnquist B, Dong X, Meyer RA, Ringkamp M (2014) Three functionally distinct classes of C-fibre nociceptors in primates Nat Commun 5:4122 doi:10.1038/ncomms5122 Yamaguchi J, Aihara M, Kobayashi Y, Kambara T, Ikezawa Z (2009) Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis J Dermatol Sci 53(1):48–54 Index A Acetylcholine (Ach), 201–202 Acute cutaneous inflammation pathways, 198 pharmacology, 197–198 Acute pain, 148–149 See also Endocannabinoid (EC) system Adenosine, 197 Adenosine monophosphate-activated protein kinase (AMPK), 22 α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor, 215 Amygdala, 7, 11 circuitry, 262–264 LA-BLA and CeA, 264 pharmacology of amino acid neurotransmitters, 266 CGRP, 274–275 CRF, 275–277 GABA, 272–273 ionotropic glutamate receptors, 266–268 metabotropic glutamate receptors, 268–272 NPS, 277–278 plasticity electrophysiological studies, 264 excitatory transmission, 265–266 neuronal activity changes, 265 output, 26 Analgesics new Nav1.7 channel, 52–53 postsurgery pain, 30 sex differences in, 227–228 Anandamide (AEA), 124, 125 Anterolateral tract (ALT), 173 2-arachidonoyl glycerol (2-AG), 124, 125 Astrocytes, 210–211 classification, 148 origin, 147 physiological conditions, 148 ATP, 219–220 Atypical PKC (aPKC) intrathecal injection of, 25, 27 LTP, 24, 25 pep2m, 26 PKMζ, 24 role of, 25 ZIP, 26 B Blood–brain barrier (BBB) endothelial cells, 211 permeable pharmacotherapies, 229 Brain derived neurotropic factor (BDNF), 24, 26–27 C Calcitonin gene-related peptide (CGRP), 173 antinociceptive effects of, 275 electrophysiological data, 274 functional receptors, 274 during migraine attacks, 226 stereotaxic administration of, 274–275 Cannabinoids CB1 receptor, 123–124 definition, 121 Cannabinoid type receptor (CB2 receptor) activation of, 124 modulation of, 130 role of, 128–129 Cardiovascular system, 243–244 Chemokine ligand (CCL2), 217 # Springer-Verlag Berlin Heidelberg 2015 H.-G Schaible (ed.), Pain Control, Handbook of Experimental Pharmacology 227, DOI 10.1007/978-3-662-46450-2 303 304 Chemokine ligand (CCL5), 223 Central immune cell non-stereoselective activation, 213 signalling, 208 synergy, 211 Central nervous system (CNS) astrocytes, 210–211 CB1 receptor, 123 cytokines, 213–215 microglia, 210 (see also Microglia) non-neuronal cell intracellular signalling in, 209 Central sensitization definition, in chronic pain animal studies on, 81 conditions, 80–81 extraterritorial manifestations of, 82–83 local ipsilateral, 82 treatment of, 80 widespread manifestations of, 83–84 itch (see also Itch) exact mechanisms and roles of, 294 mechanical hyperalgesia, 293 pruriceptors ongoing activity, 294 punctate hyperalgesia, 293 pain, 293–295 Quantitative sensory testing (QST) for assessment methods, 84 descending pain modulation, 90–91 different protocols, 84 localized vs general hyperalgesia problem, 85–86 offset analgesia, 91–92 provoked facilitation, 86, 87 referred pain, 92–93 reflex receptive fields, 89–90 spatial summation, 89 temporal summation and aftersensation, 86–88 cGMP signaling, 108–110 Chemokines, 216–217 Cholecystokinin (CCK), 217–219 Chronic constriction injury (CCI), 62, 180 Chronic inflammation, 295–296 Chronic pain EC in, 128–129 spinal cord, in neuropathic and inflammatory pain, 148–149 c-Jun N-terminal kinase (JNK) in astrocytes, 209 phosphorylation of, 158 Collagen-induced arthritis (CIA), 159 Index Corticotropin-releasing factor (CRF) changes of, 276–277 effects of, 277 electrophysiological studies, 275 endogenous receptor activation, 276, 277 extrahypothalamic expression of, 275 patch-clamp analysis, 276 receptor antagonist, 275 sources of, 275 CPEB See Cytoplasmic polyadenylation element-binding protein (CPEB) Crosstalk, receptor, 222–225 Cuff-algometry technology, 89 Cutaneous mechanical hyperalgesia, 60 CX3LC1 (Fraktalkine)/R1, 153–154 C-X-C chemokine receptor (CXCR1), 223 C-X-C chemokine receptor (CXCR2), 223 C-X-C chemokine receptor (CXCR4), 224 CX3C (Fractalkine) receptor-1 (CX3CR1), 216, 224 Cytokine-mediated neuronal excitation, 215–216 Cytokines, 213–215 Cytoplasmic polyadenylation element-binding protein (CPEB), 23, 24 D Delayed onset muscle soreness (DOMS), 63–65 Descending pain modulation, 90–91 Desensitisation, 222, 243 Diacylglycerol lipase-α (DAGLα), 125, 127 Dorsal root ganglia (DRG), 41 Dorsal root reflex (DRR) glial dependence of, 196–197 spinal cord modulation of peripheral inflammation, 193–194 E Endocannabinoid (EC) system acute pain processing, 127–128 CB2 receptors (see Cannabinoid type receptor (CB2 receptor)) comparison of classical neurotransmitter systems, 121 endogenous ligands, 124 notional neuronal synapse, signalling, 122 and pain, 125–126 and peripheral pain processing, 126–127 plasticity problems, 132–133 supraspinal level, 130–132 synthesis and degradation, 124–125 Index Endothelial NOS (eNOS or NOS-3), 104, 105 Epac signaling, 22 Extracellular signalregulated kinase (ERK), 21 F Familial episodic pain (Nav1.9), 48, 50–51 Fascia, 61–62 Fatty acid amide hydrolase (FAAH), 126–127, 133 Fractalkine, 216–217 Fragile X mental retardation protein (FMRP), 22–23 Functional magnetic resonance imaging (fMRI), 131, 132 G GABAergic neurons, 183–184 Gamma(γ)-aminobutyric acid (GABA) amygdala, pharmacology of, 272–273 immunostaining for, 175 receptors, 215 spinal cord modulation of peripheral inflammation, 193–194 Gastrointestinal system, 245, 252 Glia, 211 activation, 214–215 origin and function of, 146–148 spinal changes (see Neuropathic pain) Glycinergic circuits, 185–186 G protein-coupled receptor (GPCR), 121, 216, 222 H Hereditary and sensory autonomic neuropathy type IID (HSANIID), 48 Heterologous desensitisation, 222 Heteromerisation, 223–224 Homologous desensitisation, 222 Human heritable sodium channelopathy familial episodic pain (Nav1.9), 50–51 inherited primary erythromelalgia (Nav1.7), 47–49 pain insensitivity (Nav1.7 and Nav1.9), 51–52 pain-related, 47 paroxysmal extreme pain disorder (Nav1.7), 49 selective Nav1.7 analgesics, 52–53 small fibre neuropathy (Nav1.7 and Nav1.8), 49–50 Hyperalgesic priming CNS regulation of 305 atypical PKCs, 24–27 BDNF, 24–27 endogenous opioids, 27–29 μ-opioid receptor constitutive activity, 27–29 opioid effects, 29–30 surgery as priming stimulus, 29–30 in messenger signaling pathways, 19 therapeutic opportunities, 31–32 translational control pathways involved in, 21 I IL-1 receptor antagonist (IL-1ra), 214 Immune signalling central, 214, 215, 229 in central nervous system, 208 homeostatic, 214 neuron–glial central, 217 Immuno-active agents, 196–197 Immunocompetent cells, in opioid pharmacodynamics, 211 Inducible nitric oxide synthase (iNOS) isoform, 220 Inducible NOS (iNOS or NOS-2), 104 Inflammation acute cutaneous pathways, 198 pharmacology, 197–198 acute joint models, 196–197 characteristics, 157 chronic itch, 295–296 chronic models of pathways, 200 pharmacology, 199 JNK phosphorylation, 158 monoarthritis-kaolin/carrageenan knee, 195–196 nervous system effects, and neuropathic pain, 149–150 PAR1, 247 PAR2, 248–250 PAR3, 250 PAR4, 250 in pathophysiologic nociceptive pain, role of, 157 spinal glia mechanisms, 158 sympathetic terminals in, 200–201 Inherited primary erythromelalgia (IEM), 47–49 Interleukin (IL-6), 22 Interleukin-1β (IL-1β), 156–157 Interleukin-1receptor (IL-1R), 156–157 306 Interneurons excitatory, 175–176 inhibitory, 174–175 loss, 182–183 reduced excitation of, 184–185 Ionotropic glutamate receptors, 266–268 Itch central sensitization exact mechanisms and roles of, 294 mechanical hyperalgesia, 293 pruriceptors ongoing activity, 294 punctate hyperalgesia, 293 intensity and pattern theory activated nociceptors, 291–293 non-histaminergic itch, 290–291 mechanisms for, 295–296 peripheral sensitization, 295 specificity for antagonistic interaction, 288–290 molecular markers, 287–288 L Laterocapsular division of central nucleus of amygdala (CeLC) evoked responses, 268, 271 excitatory synaptic transmission, 265 glutamatergic inputs, 266–267 hyperactivity of, 267 stimulus-evoked activity, 264 synaptic inhibition, 271–272 Long-term potentiation (LTP), 7, 23, 24 Low-threshold mechanoreceptors (LTMRs), 177 M Manganese superoxide dismutase (MnSOD), 221 Mechanistic target of rapamycin complex (mTORC1), 21 Medication-overuse headache, 226 Metabotropic glutamate receptors (mGluRs) activation of, 270, 271 DCPG, 272 electrophysiological analysis, 270, 271 facilitatory effects of, 269–270 pattern of, 269 presynaptic receptors, 271 role of, 268 types, 268, 270, 271 ZJ43, 271 Index Microglia, 210 cell populations, 147–148 monocytic/myeloid origins, 146 phagocytes of, 147 physiological conditions, 147 roles, 147 Mitogen-activated protein (MAP), 202 Mitogen-activated protein kinase (MAPK) signalling pathway, 209 Monoacylglycerol lipase (MAGL), 127, 128 Monoarthritis-Kaolin/Carrageenan knee, 195–196 Monocyte chemoattractant protein-1 (MCP-1), 217 mTORC1 See Mechanistic target of rapamycin complex (mTORC1) μ-opioid receptor (MOR), 27–28, 209 Muscular mechanical hyperalgesia, 60, 61 Musculoskeletal system, 246–247 Myelinated nociceptors, 173 N N-acylethanolamines (NAEs), 125 Nacyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), 125 Naltrexone, 224 Natriuretic peptide receptor A (NPR-A), 108 Nav1.3, 46–47 Nav1.7 inherited primary erythromelalgia, 47–49 new selective analgesics, 52–53 pain insensitivity, 51–52 paroxysmal extreme pain disorder, 49 rodent studies, insights from, 41, 45 small fibre neuropathy, 49–50 Nav1.8 rodent studies, insights from, 45–46 small fibre neuropathy, 49–50 Nav1.9 familial episodic pain, 50–51 pain insensitivity, 51–52 rodent studies, insights from, 46 Nerve growth factor (NGF), 22 action mechanism acute sensitization, 68–69 long-lasting sensitization, 69 mechanical stimuli sensitization, 70–71 cachexia pain, 67 cancer pain, 67 inflammatory pain, 62 musculoskeletal pain cast immobilization, 65–66 Index DOMS, 63–65 osteoarthritis models, 65–66 neuropathic pain, 62–63 nociceptive system development, 59 nociceptor activities and axonal properties, 67–68 pain and mechanical/thermal hyperalgesia induced animals, 60 humans, 60–62 receptor, 58–59 and receptor trkA, 9–10 therapeutic perspective, 71 visceral painful conditions, 66 Nervous system, 244–245 Neuroglia, 146 Neuronal NOS (nNOS or NOS-1), 104, 105 Neuropathic pain animal models of, 180–181 astrocytic responses, to injury, 152 cathepsin S, 153–154 CX3CL1/R1, 153–154 definition, IL-1β, 156–157 IL-1R, 156–157 inflammatory pain and, 149–150 microglial responses to injury, 150–151 neuronal mechanisms of, 5–8 PAR1, 251 PAR2, 251, 252 PAR3 and PAR4, 252 possible mechanisms, reduced inhibition of GABAergic neurons, 183–184 glycinergic circuits role, 185–186 inhibitory interneurons excitation, 184–185 inhibitory interneurons loss, 182–183 inhibitory transmission effectiveness, 185 process of, reduced inhibitory synaptic transmission in, 181 TNF, 154–155 TNFR, 154–155 Neuropathy, 295–296 Neuropeptide CGRP, 274–275 CRF, 275–277 NPS, 277–278 Neuropeptide S (NPS), 277–278 NGF See Nerve growth factor (NGF) NG-nitro-L-arginine (L-NOARG), 220 307 NG-nitro-L-arginine methyl ester (L-NAME), 220 Nitric oxide (NO), 220 Nitric oxide (NO)-mediated pain processing in dorsal root ganglia, 104–105 downstream mechanisms of cGMP signaling, 108–110 NO-GC activation, 107–108 peroxynitrite formation, 110–111 S-nitrosylation, 110 pro-and antinociceptive functions of, 105–106 in spinal cord, 104–105 Nitric oxide(NO)-sensitive guanylyl cyclase (NO-GC), 107–108 Nitric oxide synthase (NOS), 220 inhibitors, 105–106 isoforms, 104 N-methyl-D-aspartate (NMDA) receptors, 28 Nociceptive system acute sensitization direct phosphorylation by TrkA, 68–69 indirect action of, 69 membrane trafficking of TRPV1, 69 sympathetic nerve involvement, 69 central, descending system, development, 59 long-lasting sensitization to heat, 69 mechanical stimuli sensitization mechanical hyperalgesia, 70 mechanical hypersensitivity, 70 TrkA, 70–71 molecular mechanisms of, 8–11 peripheral, thalamocortical system, Nociceptor priming animal models, 18 chronic pain conditions, 18 hyperalgesic priming (see Hyperalgesic priming) local translation, key mediator of, 20 CPEB, 23 epac signaling, 22 experimental paradigm, 23 FMRP, 23 PKCε-induced priming, 24 in sensory neurons, 22 translation, 21 naăve rodents, 18 PKC, crucial mechanism of, 19–20 preclinical models, 16 prostaglandins, 18 308 Non-neuronal cell intracellular signalling, 208, 209 Non-neuronal central immune cells, 209 astrocytes, 210–211 central immune synergy, 211 microglia, 210 O Offset analgesia, 91–92 Opioid-induced cytokine signalling, 225–226 Opioid-induced initiation analgesia opposition ATP, 219–220 chemokines, 216–217 cholecystokinin, 217–219 cytokines, 213–215 nitric oxide, 220 potentiating/unmasking, 214 proinflammatory cytokine-mediated neuronal excitation, 215–216 sphingomyelins, 220–222 gonadal hormone contribution, 228 Opioid-overuse headache, 225–226 Opioids, 208 pharmacodynamics, 211 tolerance, 208, 209, 218 P Pain insensitivity (Nav1.7 and Nav1.9), 51–52 Paroxysmal extreme pain disorder (PEPD), 48, 49 Pathophysiologic nociceptive pain definition, Periaqueductal grey matter (PAG), 130–131, 217 Peripheral nerve injury See Neuropathic pain Peripheral nervous system (PNS) CB1 receptor, 123 targeting, 31 Peripheral nociceptive system, Peripheral pain processing, EC system, 126–127 Peripheral sensitization molecular mechanisms of, 5–6 pain, 295 Peroxynitrite, 221 Phosphoinositide 3-kinases (PI3Ks), 249 Physiologic nociceptive pain, Postherpetic neuralgia (PHN), 82 Primary afferent axons, 172–173 Primary afferent depolarization (PAD), 193–194 Proinflammatory cytokine-mediated neuronal excitation, 215–216 Proinflammatory cytokines, 214 Index Projection neurons in anterior lateral tract (ALT), 173, 176–177 selective innervation of, 178 Proteases categories, 240 proteolytic properties, 240 Proteinase-activated receptor (PAR), 10 activating peptides and antagonists, 241 activation, 240–242 cardiovascular system, 243–244 cleaving enzymes, 241 definition, 240 desensitisation mechanisms, 243 drug target for pain, 253–254 gastrointestinal system, 245 and inflammatory pain, 247–250 musculoskeletal system, 246–247 nervous system, 244–245 neuropathic pain, 250–252 signalling PAR1, 242 PAR2, 243 PAR3 and PAR4, 243 Protein kinase A (PKA), 19 Protein kinase G (PKG), 108 Protein kinase M zeta (PKMζ), 24 Provoked central sensitization, 86, 87 Punctate hyperalgesia, 293 P2X4 receptors, 219 Q Quantitative sensory testing (QST) assessment methods, 84 descending pain modulation, 90–91 different protocols, 84 localized vs general hyperalgesia problem, 85–86 offset analgesia, 91–92 provoked facilitation, 86, 87 referred pain, 92–93 reflex receptive fields, 89–90 spatial summation, 89 temporal summation and aftersensation, 86–88 R Receptor activity-modifying protein (RAMP1), 274 Receptor binding non-stereoselective, 212–213 Receptor crosstalk, molecular mechanisms of, 222–225 Index Referred pain, 92–93 Reflex receptive fields, 89–90 Rheumatoid arthritis (RA) pain analgesic effect of, 160 characteristics, 158 clinical signs of, 158 poly-arthritic rodent models, 159 spinal microglia role, 160 treatment of, 159 Rhizotomy, 192–193 Rostral ventromedial medulla (RVM) and cholecystokinin, 218 excitatory projections to, 131 microinjection, of cannabinoid agonists, 130 S SCN9A gene, 47, 48, 50 SCN10A gene, 47 SCN11A gene, 47, 50 Seven-transmembrane (7TM) receptors, 222 Small fibre neuropathy (SFN), 49–50 S-nitrosylation, 110 Sodium channels Nav1.3, 46–47 (see also Nav1.3) Nav1.7, 41, 45 (see also Nav1.7) Nav1.8, 45–46 (see also Nav1.8) Nav1.9, 46 (see also Nav1.9) Nav transgenic mice studies, 41–44 Soluble guanylyl cyclase (sGC), 107 Spared nerve injury (SNI), 181 Spatial summation, 89 Sphingomyelins, 220–222 Sphingosine, 220 Sphingosine kinases (SphK) and 2, 220–221 Spinal cord excitatory synaptic transmission in, 10 mechanisms, 10–11 nociceptive neurons in, Spinal cord inhibitory mechanisms descending pathways, 176 neurons and circuits interneurons, 174–176 normal function of inhibitory mechanisms, 179–180 presynaptic inhibitory, 179 primary afferents, 172–173 projection neurons, 173–174 selective innervation of, 178 synaptic connections, 176, 177 neuropathic pain animal models, 180–181 possible mechanisms, 181–186 309 reduced inhibitory synaptic transmission in, 181 Spinal cord modulation of peripheral inflammation acute cutaneous inflammation, 197–198 acute inflammatory models, 195–196 chronic models of, 199–200 dorsal root reflex, 193–194 joint inflammation, 196–197 rhizotomy, 192–193 spinovagal circuitry, 201–202 sympathetic effects on, 200–201 Spinal endocannabinoid system See Endocannabinoid (EC) system Spinal glia See also Neuropathic pain during inflammatory pain, 157–158 during rheumatoid arthritis pain, 158–160 Spinal immune cell function, 130 Spinal nerve ligation (SNL), 181 Spinal sensitization, Spinovagal circuitry, 201–202 Stereoselective receptor binding, 212–213 Superoxide dismutase (SOD), 221 Sympathectomy, 200, 201 T Temporal summation and aftersensation, 86–88 Terminal deoxynucleotidyl transferasemediatedbiotinylated UTP nick end labelling (TUNEL), 182 Thalamocortical system, nociceptive neurons in, 4–5 Toll-like receptor-4 (TLR4) LPS activation, 222 medication-overuse headache, 226 in non-stereoselective binding, 213 opioids and, 228 Toll-like receptors (TLRs), 226 Tropomyosin-related kinase A (TrkA) direct phosphorylation by, 68–69 mechanical stimuli sensitization, 70–71 membrane trafficking of TRPV1 by, 69 Tumor necrosis factor (TNF) spinal cord, in neuropathic and inflammatory pain, 154–155 spinal pretreatment with, 196 V Voltage-gated sodium channels (VGSCs) alpha subunit, primary structure of, 40, 41 mammalian, 40 ... proteins CD1 72, CD200R and CD45 with their neuronal ligands CD47, CD200 and CD 22, respectively (Ransohoff and Perry 20 09; Ransohoff and Cardona 20 10; Cardona et al 20 06; Saijo and Glass 20 11) Within... et al 20 01; Tsuda et al 20 03, 20 12; Davalos et al 20 05) Microglial P2X4 is of particular importance for the development of neuropathic pain; it is upregulated in microglia as early as 24 hours... Ebersberger A (20 12) Spinal interleukin-6 is an amplifier of arthritic pain in the rat Arthritis Rheum 64 :22 33 22 42 Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (20 04) Fractalkine